Recent experimental and clinical studies have established that vascular inflammation is central to the nonvascular and vascular aging. To date studies with mostly single occasion assessments of markers or single nucleotide polymorphisms (SNPs) have suggested that variation in inflammatory pathway markers and SNPs are associated with the aging process and subclinical CVD. However, the studies have differed with regard to which markers and genes are central, and have left questions as to whether inflammation begets aging and subclinical CVD, whether aging and subclinical CVD lead to inflammation. We previously measured 11 systemic biomarkers and 3000 SNPs in over 200 candidate genes in inflammatory pathways in the community-based Framingham Offspring sample. The 3500 middle-aged and elderly men and women receive serial phenotyping for age-related phenotypes including physical function, CVD risk factors, and subclinical and clinical CVD. The extent to which inflammatory biomarkers increase with advancing age, independent of age-related CVD and its risk factors is uncertain. The relation of variation in inflammatory genes to aging-related phenotypes, including frailty, physical function and subclinical CVD is largely unknown. The central hypothesis of this proposal is that the acceleration of systemic inflammation in midlife and advanced age is influenced by both risk factors and genetic variation. We postulate that variation in inflammatory pathway genes modulates longitudinal changes in inflammatory markers, and vascular aging (as assessed by increasing blood pressure and subclinical CVD), and the progression of frailty and declining physical function. To address these hypotheses we propose to repeat at the measurements of 7 key inflammatory biomarkers, originally assessed 7 years. Specific Aims: Aim 1. To examine the risk factors related to 7 year progression of systemic inflammation (between Offspring examinations 7 and 8, and Omni exams 2 &3) in the community. Aim 2. To investigate the genetic factors associated with systemic inflammation and to examine the relation between inflammatory SNPs/haplotypes and frailty and declining physical function. Aim 3. To study the relation of changes in inflammatory markers to progression of blood pressure and subclinical disease including ankle brachial index, arterial tonometry, echocardiographic left ventricular structure and function and carotid intimal medial thickness. Aim 4. To identify the relations between changes in inflammatory biomarkers to frailty and progression of declining physical function over 7 years of follow-up. The proposed study will fundamentally contribute insight about the relations of inflammation and aging.